Chemoselective deprotection of triethylsilyl ethers

Article abstract of DOI:10.1080/15257770903362172

An efficient and selective method was developed for the deprotection of triethylsilyl (TES) ethers using formic acid in methanol (5-10%) or in methylene chloride 2-5%) with excellent yields. TES ethers are selectively deprotected to the corresponding alco

Full text of DOI:10.1080/15257770903362172

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Chemoselective Deprotection of
Triethylsilyl Ethers
Tilak Chandra a , William E. Broderick a & Joan B. Broderick a
a Department of Chemistry and Biochemistry Montana State
University, Bozeman, Montana, USA
Published online: 24 Nov 2009.
To cite this article: Tilak Chandra , William E. Broderick & Joan B. Broderick (2009): Chemoselective
Deprotection of Triethylsilyl Ethers, Nucleosides, Nucleotides and Nucleic Acids, 28:11-12, 1016-1029
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Nucleosides, Nucleotides and Nucleic Acids, 28:1016–1029, 2009
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770903362172
CHEMOSELECTIVE DEPROTECTION OF TRIETHYLSILYL ETHERS
Tilak Chandra, William E. Broderick, and Joan B. Broderick
Department of Chemistry and Biochemistry Montana State University, Bozeman,
Montana, USA
An efficient and selective method was developed for the deprotection of triethylsilyl (TES) ethers
2
using formic acid in methanol (5–10%) or in methylene chloride 2–5%) with excellent yields. TES
ethers are selectively deprotected to the corresponding alcohols in high yields using formic acid in
methanol under mild reaction conditions. Other hydroxyl protecting groups like t-butyldimethylsilyl
(TBDMS) remain unaffected.
Keywords Chemoselective; dinucleosides; spore photoproduct; S-adenosylmethionine;
spore photoproduct lyase
INTRODUCTION
Selective and efficient protection and deprotection plays a central role
in the completion of multistep syntheses of organic molecules. For exam-
ple, trityl,[1] triethylsilyl,[2] and tert-butyldimethylsilyl[3] ethers are normally
used for selective protection of primary/secondary alcohols, particularly in
carbohydrate and nucleoside/nucleotide chemistry. However, despite the
ubiquity of these protecting groups in organic synthesis, only a few methods
exist for selectively deprotecting them.[4] The selective deprotection of
triethylsilyl (TES) ethers in the presence of tert-butyldimethylsilyl (TBDMS)
can be carried out using 10% Pd/C in methanol or 95% ethanol,[5] meso-
porous silica MCM-41/MeOH,[6] IBX in dimethyl sulfoxide (DMSO),[7] and
1-chloroethyl chloroformate in methanol.[8] These methods work well in
many cases, however all require expensive reagents or catalysts. Our interest
in synthesizing 5,6-dihydro-5-(α-thyminyl)-thymine has led us to develop a
Received 29 April 2009; accepted 14 September 2009.
The authors gratefully acknowledge support for this work from the National Institute of Health
(GM67804).
Address correspondence to Joan B. Broderick, Department of Chemistry and Biochemistry
Montana State University, Bozeman, MT, 59717, USA. E-mail: jbroderick@chemistry.montana.edu
1016

Chemoselective Deprotection of triethylsilyl Ethers
1017
O
O
N
NH
NH
O
P
O
O
O
O
N
O
O
6 5
O
O
6 5
O
O
O
O
Me
CH2
H
Me
Me
hv
P
H
_O
_O
SP lyase
O
N
O
O
N
O
O
NH
NH
O
O
SP
SCHEME 1 Formation and Repair of SP.
new method for the chemoselective deprotection of triethylsilyl ethers that
is both efficient and economical.
5,6-Dihydro-5-(α-thyminyl)-thymine, or spore photoproduct (SP), is a
methylene-bridged thymine dimer formed in spore DNA on ultraviolet
(UV) irradiation (Scheme 1).[9,10] SP is the primary DNA photoproduct of
UV irradiation of bacterial spores, and the extreme UV resistance of bacte-
rial spores is due in part to the efficient repair of SP on spore germination.
The repair of SP is catalyzed by the enzyme spore photoproduct lyase (SPL),
which utilizes an iron-sulfur cluster and S-adenosylmethionine (AdoMet) to
generate a putative 5ꢁ-deoxyadenosyl radical intermediate, which abstracts a
hydrogen atom from C-6 of SP to initiate a radical-mediated β-scission.[11–14]
Developing an understanding of the DNA repair mechanism of SPL has
been hindered due to the unavailability of the pure spore photoproduct; in
fact, most enzymatic studies in the literature involve the use of UV-irradiated
DNA—an inherently impure substance containing numerous different types
of damage—as a substrate. Currently, only limited synthetic routes are
available in the literature for the generation of pure spore photoproduct
with a phosphodiester linkage.[15] Our ongoing efforts to understand the
SPL mechanism have led us to develop efficient methods for the synthesis
of SP.
RESULTS AND DISCUSSION
We report here an efficient and cost effective method for making
the 5R and 5S-diastereomers of SP in high yields (Scheme 2) and their
subsequent deprotection under mild reaction conditions (Scheme 3). The
protected 5R and 5S-diastereomers (3 and 4) were prepared by coupling N3-
trimethylsilylethoxymethyl-3, 5-di-triethylsilyl-5,6-dihydrothymidine 1 and 2-
bromomethyl uridine 2 using lithium diisopropyl amide (LDA) as a con-
densing reagent[15] at −78◦C, which afforded 5R and 5S-diastereomers in a
3:4 ratio (Scheme 2). The 5R and 5S-diastereomers were easily purified on

1018
T. Chandra et al.
O
N
O
Me
O
N
O
N
SEM
SEM
5
N
N
SEM
Me
SEM
Br
6
N
N
O
N
O
LDA, THF,
H
O
O
H
H
O
O
-78 oC, 3 - 4 h
+
RO
SETO
O
O
OTBDMS
OTES
R = TBDMS
SETO
OTBDMS
SETO
RO
3
1
2
+
O
O
Me
SEM
SEM
5
N
N
6
N
O
O
H
H
N
O
O
OTBDMS
OTES
SETO
OTBDMS
4
SCHEME 2 Formation of 5R and 5S-diastereomers.
a silica gel column using a gradient of ethyl acetate and hexanes. The struc-
tures of these two closely related compounds were assigned on the basis of
1H and 13C NMR (Table 1) as well as mass spectrometry, and the stereochem-
ical assignments were made on the basis of two-dimensional nuclear Over-
hauser enhancement spectroscopy (NOESY) and rotational nuclear Over-
hauser effect spectroscopy (ROESY) data.[16] The C-5 methyl carbon of the
5R isomer (3) was observed at 22.03 ppm, whereas the methyl carbon of the
5S- isomer (4) was shifted 1.3 ppm to higher field at 20.73 ppm. However,
only 0.04 ppm difference was observed in 1H NMR of the 5R and 5S-isomers
1
for the C-5 methyl group (Table 1). Differences in H (at C-6 and the
methylene bridge) and 13C (at C-5, C-6, and the methylene bridge) chemical
shifts for the 5R and 5S isomers were also observed (Table 1).
The synthesis of SP from 3 and 4 involves the formation of a phos-
phodiester linkage between the sugar groups; this requires the selective
deprotection of the 3ꢁ and 5ꢁ-hydroxyls of 3 and 4. In this case, TES ethers
O
N
O
N
O
N
Me
O
N
Me
SEM
SEM
SEM
SEM
N
N
N
N
5% Formic acid in
methanol
3 or 4
O
or
O
O
H
O
H
H
H
O
O
O
O
OTBDMS
OTBDMS
OH
OH
HO
OTBDMS
HO
OTBDMS
5
6
SCHEME 3 Selective deprotection of triethylsilyl ether using formic acid:methanol/methylene
chloride.

1019

1020
T. Chandra et al.
must be deprotected selectively in the presence of TBDMS ethers. We
have developed an efficient method for the deprotection of TES ethers
in the presence of TBDMS ethers using 5–10% formic acid. Formic acid
has been extensively used in carbohydrate chemistry/nucleoside chemistry
as a deprotecting agent for trityl[17a] and isopropylidene[17b–d] groups, but
so far no selective deprotection has been reported for TES versus TBDMS
groups using formic acid. The 5R and 5S-protected thymidine dinucleosides
3 and 4 were prepared and separated in high yields as described above.
Reaction of the protected dinucleosides of thymidine (3 and 4) separately
with 5–10% formic acid:methanol at ambient temperature (Scheme 3),
afforded 3ꢁ,5ꢁ-TES deprotected dinucleosides 5 and 6 in 70–85% yields.
The 3ꢁ and 5ꢁ TBDMS groups of the dinucleosides remain unaffected
under these reaction conditions (Table 2). The crude reaction mixture
after workup showed only the desired product without any undesired
side products. Reaction progress was conveniently monitored via thin-layer
1
chromatography (TLC) and H NMR, and the deprotection was generally
complete within 2–3 hours.
The deprotection of TES ethers generally proceeded more quickly
in protic solvents than in nonprotic solvents. The deprotection reactions
in methylene chloride were sluggish, with complete deprotection of TES
ethers taking 20–24 hours (Table 2), consequently resulting in lower yields
of the desired dinucleosides (50–60%). Under higher concentration of the
formic acid in methanol (up to 20%), no deglycosylation or decomposition
of the desired product was observed.
Triethylsilyl ethers can be easily deprotected in the presence of tert-
butyldimethylsilyl ethers using 2% HF in acetonitrile or pyridine.[18] De-
protection of TES ethers of the thymidine dinucleosides 3 and 4 with 2–4%
HF-pyridine resulted in only ∼20–50% of the desired dinucleosides 5 and
6, along with primary (7, 9) and secondary (8, 10) TBDMS deprotected
side products (Scheme 4). The structures of 5, 6, and the side prod-
ucts were easily deduced using one- and two-dimensional NMR methods.
Higher concentrations of HF:pyridine and longer reaction times produce
completely TBDMS/TES-desilylated products. Ultimately, the HF-pyridine
method resulted in low yields of the desired thymidine dinucleoside for
further synthesis of spore photoproduct.
The formic acid:methanol combination also works well for the
selective deprotection of mononucleosides. 3ꢁ-O-tert-Butyldimethylsilyl-5ꢁ-
O-triethylsilylthymidine 13 and 3ꢁ-O-tert-butyldimethylsilyl-5ꢁ-O-triethylsilyl-
adenosine 17 were selectively deprotected in 70–76% yields using 5% formic
acid:methanol (Scheme 5). Compound 13 was prepared from thymidine
11 in two steps. In first step, thymidine was selectively protected using
0.9 equivalents of triethylsilyl chloride in 95% yields followed by protection
at the 3ꢁ hydroxyl with tert-butyldimethylsilyl chloride. Compound 17 was

1021

1022
T. Chandra et al.
O
N
O
N
Me
O
N
O
N
O
N
Me
O
N
Me
SEM
SEM
SEM
SEM
SEM
SEM
N
N
N
N
N
N
O
O
H
O
O
O
H
O
H
4% HF In
pyridine
+
+
3
H
H
H
O
O
O
O
O
O
OH
OTBDMS
OTBDMS
(5;16%)
OTBDMS
OH
OH
OH
HO
OH
HO
HO
OH
(7; 32%)
(8; 6 -10%)
O
N
O
N
Me
O
N
O
N
O
N
Me
O
N
Me
SEM
SEM
SEM
SEM
SEM
SEM
N
N
N
N
N
N
O
O
H
H
O
O
O
H
O
H
H
4% HF In
pyridine
+
+
4
H
O
O
O
O
O
O
OH
OTBDMS
OTBDMS
OH
OH
OH
HO
OH
HO
HO
OTBDMS
OH
(6; 20%)
(10; 15%)
(9; 30%)
SCHEME 4 Deprotection 5R & 5S-diastereomers (3 and 4) using 4% HF: pyridine.
also prepared similarly as described for 13. Deprotection using formic acid
in methanol afforded compounds 14 and 18 in excellent yields (Scheme 5).
As control reactions, the 3ꢁ and 5ꢁ TBDMS-protected thymidine
19, the fully protected thymidine 20 (N 3-Trimethylsilylethoxymethyl-3ꢁ,
5ꢁ-di-t-butyldimethylsilyl thymidine), and the 3ꢁ and 5ꢁ TES-protected
O
N
O
N
O
N
O
N
Me
Me
Me
Me
HN
HN
HN
HN
(i)
(ii)
(iii)
O
O
O
O
O
HO
O
O
O
SETO
HO
SETO
HO
OTBDMS
13
HO
OTBDMS
14
12
11
NH2
NH2
N
NH2
N
NH2
N
N
N
N
N
N
(iii)
N
(ii)
(i)
N
N
N
N
N
N
N
SETO
HO
SETO
HO
O
O
O
O
OH
OH
15
Reagents and Conditions:
(i) TESCl, DMF, Imidazole, 95% (ii) TBDMSCl, DMF, Imidazole, rt., 93% (iii) MeOH:Formic acid, rt, 72-76%.
SCHEME 5 Selective deprotection of protected thymidine and adenosine.
OTBDMS
18
OTBDMS
17
16

Chemoselective Deprotection of triethylsilyl Ethers
1023
dihydrothymidine 21 were stirred in 5–10% formic acid in methanol for
3–5 hours. NMR spectra of the reaction mixtures for 19 and 20 reveals
that the TBDMS groups remain intact (Scheme 6). Even at higher con-
centrations of formic acid:methanol and over longer reaction periods,
no deprotection of TBDMS was observed. In contrast, the TES-protected
dihydrothymidine 3ꢁ, 5ꢁ-O-di-triethylsilyl-5, 6-dihydrothymidine (21), is de-
protected in high yields under the same reaction conditions (Scheme 6).
EXPERIMENTAL
All reactions were carried out in oven- or flame-dried glassware under a
nitrogen atmosphere. Solvents were distilled prior to use. Dichloromethane
and pyridine were distilled from calcium hydride. Tetrahydrofuran (THF)
was distilled on sodium/benzophenone prior to use. Purification of reaction
products was carried out by flash chromatography using silica gel (230–
400 mesh). All reagents were commercially available and used without
further purification. All reactions were monitored by TLC using silica
gel 60, F-254. Column chromatography was conducted using flash silica
1
gel. H NMR and 13C NMR spectra were recorded on Bruker DPX-300,
Bruker DRX-500, or on Bruker DRX-600 (Bruker, Billerica, MA, USA). NMR
spectra were recorded on solutions in deuterated chloroform (CDCl3), with
1
residual chloroform (δ 7.27 ppm for H NMR and δ 77.0 ppm for 13C
NMR) or deuterated dimethyl sulfoxide (DMSO-d6), with residual methyl
1
sulfoxide (δ 2.50 ppm for H NMR and δ 35.0 ppm for 13C NMR) taken as
the standard, and were reported in parts per million (ppm). Abbreviations
for signal coupling are as follows: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet. The multiplicities of the 13C NMR signals were determined
by heteronuclear multiple quantum coherence (HMQC) and distortionless
enhancement by polarization transfer (DEPT) techniques. Mass spectra
(high resolution fast atom bombardment [FAB] or electrospray transmis-
sion [ESI]) were recorded on a Q-Tof and 70-VSEs spectrometer at Noyes
Laboratory, University of Illinois Urbana-Champaign.
General Procedures
Formic acid: Methanol Procedure for the Deprotection of TES Ethers
A solution of protected thymidine dinucleoside 3 or 4 (0.700 g,
0.58 mmol) in methanol (10 mL) was stirred at 5–10◦C for 5 minutes
followed by dropwise addition of a solution of 10% formic acid in methanol
(10 mL). After complete addition of the formic acid solution, the cooling
bath was removed and the reaction mixture was vigorously stirred for 1–2
hours at room temperature; TLC (ethyl acetate:hexanes 1:1) was used
to monitor the progress of the reaction. Upon complete desilylation of

1024
T. Chandra et al.
O
N
Me
HN
5-10%
NO REACTION
O
HCOOH:MeOH
SMDBTO
O
19
OTBDMS
O
Me
SEM
N
O
5-10%
NO REACTION
O
N
HCOOH:MeOH
SMDBTO
20
OTBDMS
O
O
Me
Me
HN
HN
5-10%
O
N
O
N
HCOOH:MeOH
O
HO
O
SETO
70%
HO
OTES
22
21
O
O
N
Me
Me
SEM
SEM
O
N
O
N
O
5-10%
O
N
HCOOH:MeOH
SETO
HO
1
23
OTES
OH
SCHEME 6 Deprotection of protected thymidine/5,6-dihydrothymidine.
TES groups to produce the dihydroxy dinucleoside, the reaction mixture
was neutralized with 10% sodium bicarbonate solution (∼20 mL) and the
solvent was removed on a rotary evaporator under reduced pressure. The
residue was dissolved in methylene chloride and washed with saturated

Chemoselective Deprotection of triethylsilyl Ethers
1025
sodium bicarbonate solution. The methylene chloride layer was dried over
anhydrous sodium sulfate, concentrated, and the residue was purified
on a silica gel column (flash chromatography) using a mixture of ethyl
acetate:hexanes (50:50), resulting in the desired product as a white fluffy
solid with 75–85% yield.
HF: Pyridine Procedure for the Deprotection of TES Ethers
A cold solution of 4% HF:pyridine (10 mL) was slowly added to a
mixture of 5R or 5S- dinucleoside 3 or 4 (0.50 g, 0.41 mmol) in pyridine
(5 mL) at 0–5◦C while stirring. The reaction mixture was stirred at ambient
temperature for 1–2 hours. The reaction progress was monitored using
TLC. After completion of the reaction, the solution was cooled and the
reaction mixture was neutralized with saturated sodium bicarbonate solu-
tion. The reaction mixture was concentrated under reduced pressure and
the residue was dissolved in a mixture of methylene chloride and water (1:1,
100 mL). The organic layer was thoroughly washed with saturated sodium
bicarbonate solution and dried over anhydrous sodium sulfate; finally, the
solvent was removed under reduced pressure. The respective residues were
loaded onto a silica gel column and the column was eluted with a 10–50%
ethyl acetate:hexanes gradient to afford the desired dinucleosides.
Compound 3. Yield: 30%; viscous oil; Rf. 0.6; 1H NMR (CDCl3): δ −0.05
(s, 9H, CH3), −0.03 (s, 9H, 3CH3), 0.06 (s, 3H, CH3), 0.07 (s, 3H, CH3),
0.08 (s, 3H, CH3), 0.086 (s, 3H, CH3), 0.5–0.64 (m, 12H, CH2), 0.87 (s,
9H, CH3), 0.89 (s, 9H, CH3), 0.89–0.91 (m, 22 H, 6CH3 TES &CH2 SEM),
1.18 (s, 3H, Me), 1.88–1.96 (m, 3H, CH2, 2ꢁ), 2.18–2.2 (m, 1H, CH, 2ꢁ),
2.60 (d, J = 14 Hz, 1H, CH2, bridge), 2.6 (d, J = 14 Hz, 1H, CH2, bridge),
3.03 (d, J = 13.5 Hz, 1H, CH2, base), 3.15 (d, J = 13.5 Hz, 1H, CH2, base),
3.52 (t, 2H, CH2, SEM), 3.56 (dd, 2H, CH2, 5ꢁ), 3.61 (dd, J = 8 Hz, 2H,
CH2, SEM), 3.7 (dd, J = 5.5 Hz, 2H, CH2, 5ꢁ), 3.7–3.79 (m, 1H, CH, 4ꢁ),
3.8 (m, 1H, 4ꢁ), 4.2–4.2 (m, 1H, 3ꢁ), 4.4 (m, 1H, 3ꢁ), 5.1 (s, 2H, NCH2,
SEM), 5.3 (s, 2H, NCH2, SEM), 6.2–6.3 (m, 2H, 1ꢁ), 7.4 (s, 1H, base); 13C
NMR (CDCl3): δ −5.4 (CH3), −5.3 (CH3), −4.8 (CH3), −4.6 (CH3), −1.4
(CH3), −1.4 (CH3), 4.2 (CH2), 4.6 (CH2), 6.7 (CH3), 6.77 (CH3), 17.9
(Cquat), 18.1 (CH2), 18.3 (Cquat), 22.0 (CH3 C5), 25.7 (Me, TBDMS),
25.9 (Me, TBDMS), 32.3 (CH2 bridge), 36.8 (CH2), 40.2 (CH2), 42.9, 44.2
(CH2-base), 62.8 (CH2), 63.0 (CH2), 66.6 (CH2), 67.4 (CH2), 69.9 (CH2,
SEM), 70.3 (CH2, SEM), 71.9 (C 3ꢁ), 72.0 (C 3ꢁ), 84.3 (C 4ꢁ), 85.3 (C, 1ꢁ),
86.2 (C 1ꢁ), 87.4 (C 4ꢁ), 108.5 (Cquat), 139.1 (CH), 150.6 (Cquat), 152.2
(Cquat), 163.4 (Cquat), 173.6 (Cquat); HRMS: m/z: 1201.7001 (calcd. for
C56H113N4O12Si6; 1201.6971) (M + H); MS: (TOF, MS, ESI) m/z 1223,
1203, 1202, 1201, 1200, 1173, 1087, 859, 858, 857, 829, 801, 629, 628, 599.
Compound 4. Yield: 40%; viscous oil; Rf. 0.5; 1H NMR (CDCl3): δ −0.48
(s, 9H, CH3), −0.03 (s, 9H, 3CH3), 0.056 (s, 3H, CH3), 0.06 (s, 3H, CH3),

1026
T. Chandra et al.
0.07 (s, 6H, 2CH3), 0.5–0.6 (m, 12H, CH2), 0.8 (s, 9H, CH3, TBDMS), 0.87
(s, 9H, CH3 TBDMS), 0.9–0.9 (m, 4 H, 2 CH2), 0.9 (s, 9H, TES), 0.9 (s, 9H,
TES), 1.1 (s, 3H, Me), 1.9–2.01 (m, 3H, CH2, 2ꢁ), 2.2 (dd, J = 7.5 Hz, 1H,
CH, 2ꢁ), 2.4 (d, J = 14 Hz, 1H, CH2, bridge), 2.7 (d, J = 14 Hz, 1H, CH2,
bridge), 3.0 (d, J = 13.5 Hz, 1H, CH2, base), 3.2 (d, J = 13.5 Hz, 1H, CH2,
base), 3.5 (t, J = 8 Hz, 2H, CH2, SEM), 3.5 (dd, 2H, CH2, 5ꢁ), 3.6 (t, J = 8.5
Hz, 2H, CH2), 3.7 (dd, 2H, CH2, 5ꢁ), 3.8 (bt, 1H, 4ꢁ), 3.91 (bt 1H, 4ꢁ), 4.2 (bt,
1H, 3ꢁ), 4.3 (bt, 1H, 3ꢁ), 5.1 (d, J = 9.5 Hz, 1H, CH2, SEM), 5.1 (d, 1H, CH2,
SEM), 5.3 (s, 2H, CH2, SEM), 6.2 (t, J = 6 Hz, 1H, 1ꢁ), 6.3 (t, 1H, 1ꢁ), 7.4
(s, 1H, base); 13C NMR (CDCl3): δ −5.4 (CH3), −5.3 (CH3), −4.8 (CH3),
−4.69 (CH3), −1.4 (CH3), 4.2 (CH2), 4.6 (CH2), 6.7 (CH3), 6.7 (CH3), 17.9
(Cquat), 18.0, 18.1, 18.3, 20.7 (CH3), 25.7 (Me), 25.8 (Me), 32.2 (CH2),
37.0 (CH2), 40.7 (CH2), 42.2 (Cquat), 44.9 (CH2-base), 63.2 (CH2), 63.3
(CH2), 66.6 (CH2), 67.3 (CH2), 69.9 (CH2), 70.0 (CH2), 70.2, 72.1, 72.6,
72.73, 84.95, 86.22, 86.72, 87.97, 108.44 (Cquat), 137.9 (CH), 150.5 (Cquat),
152.5 (Cquat), 163.3 (Cquat), 173.5 (Cquat); HRMS: m/z: 1201.7021 (calcd.
for C56H113N4O12Si6; 1201.6971) (M + H); MS: (TOF, MS, ESI) m/z 1223,
1203, 1202, 1201, 1200, 1173, 1087, 859, 858, 857, 829, 801, 629, 628, 599.
1
Compound 5. Yield: 75%; Rf. 0.4; white fluffy solid; H NMR (CDCl3):
δ −0.011 (s, 9H, CH3, SEM), −0.01 (s, 9H, 3CH3, SEM), 0.09 (s, 6H, CH3,
TBDMS), 0.1 (s, 6H, CH3), 0.8 (s, 9H, CH3), 0.8 (s, 9H, CH3), 0.9–0.9 (m,
4H, 2CH2), 1.1 (s, 3H, Me), 1.9–2.0 (m, 1H, CH2, 2ꢁ), 2.0–2.1 (m, 1H, CH,
2ꢁ), 2.2–2.27 (m, 2H, CH, 2ꢁ), 2.33 (m, 1H, OH), 2.72–2.81 (m, 2H, CH2,
bridge), 3.09 (bt, 1H, OH), 3.19 (d, J = 13 Hz, 1H, CH2, base), 3.51 (d, J
= 13 Hz, 1H, CH2, base), 3.58 (t, J = 8.5 Hz, 4H, CH2, SEM), 3.68–3.78 (m,
4H, 5ꢁ), 3.8 (q, 1H, 4ꢁ) 3.9 (q, 1H, 4ꢁ), 4.41 (m, 1H, 3ꢁ), 4.4 (m, 1H, 3ꢁ), 5.1
(d, J = 9.5 Hz, 1H, CH2, SEM), 5.2–5.2 (m, 2H, CH2, SEM), 5.4 (d, 1H, CH2,
SEM), 6.2 (t, J = 7 Hz, 1H, 1ꢁ), 6.3 (t, J = 6 Hz, 1H, 1ꢁ), 7.5 (s, 1H, base); 13
C
NMR (CDCl3): δ −5.4 (CH3), −5.3 (CH3), −4.8 (CH3), −4.7 (CH3), −1.5
(CH3), −1.4 (CH3), 17.87 (Cquat), 17.9 (CH2), 18.1 (CH2), 18.3 (Cquat),
20.8 (CH3), 25.65 (Me), 25.8 (Me), 31.8 (CH2), 37.4 (CH2), 40.6 (CH2),
42.1 (Cquat), 44.9 (CH2-base), 62.4 (CH2), 63.0 (CH2), 66.6 (CH2), 67.7
(CH2), 69.8 (CH2), 70.1 (CH2), 72.1 (CH), 72.2 (CH), 85.5 (CH), 85.6
(CH), 86.1 (CH), 87.8 (CH), 108.5 (Cquat), 139.0 (CH), 150.5 (Cquat),
152.2 (Cquat), 163.5 (Cquat), 174.2 (Cquat); HRMS: m/z: 973.5267 (calcd.
for C44H85N4O12Si4; 973.5241) (M + H); MS: (TOF, MS, ESI) m/z 995 [M +
Na], 973, 947, 946, 945, 917, 829, 801, 729; Anal. Calcd. for C44H84N4O12Si4:
C, 54.29; H, 8.70; N, 5.76; Found: C, 54.19, H, 8.74, N, 5.67.
Compound 6. The 5S-di-TBDMS dinucleoside was prepared in a similar
manner as described for compound (5). Purification was carried out using
a mixture of ethyl acetate:hexanes (50:50%) as eluent. Yield: 80%; Rf. 0.2;
white fluffy solid; 1H NMR (CDCl3): δ −0.01 (s, 9H, 3CH3 SEM), −0.02 (s,
3CH3, 9H, 3CH3, SEM), 0.08 (s, 6H, CH3, TBDMS), 0.0 (s, 3H, CH3), 0.13
(s, 3H, CH3), 0.8 (s, 9H, CH3), 0.9 (s, 9H, CH3), 0.9–0.9 (m, 4H, 2CH2),

Chemoselective Deprotection of triethylsilyl Ethers
1027
1.2 (s, 3H, Me), 1.8 (bs, 1H, OH), 1.9–2.0 (m, 1H, CH2, 2ꢁ), 2.08–2.1 (m,
1H, CH, 2ꢁ), 2.2–2.2 (m, 1H, CH, 2ꢁ), 2.2–2.3 (m, 1H, CH, 2ꢁ), 2.4 (bs, 1H,
OH), 2.6 (d, J = 14.5 Hz, 1H, CH2, bridge), 2.8 (d, J = 14.5 Hz, 1H, CH2,
bridge), 3.2 (q, 2H, CH2, base), 3.5 (t, J = 8 Hz, 4H, CH2, SEM), 3.6 (dd,
4H, CH2, 5ꢁ) 3.7 (m, 2H, 5ꢁ), 3.8 (bt, 2H, 4), 3.9 (bt, 1H, 4ꢁ), 4.3 (bt, 1H, 3ꢁ),
4.5 (bt, 1H, 3ꢁ), 5.1 (d, J = 10 Hz, 1H, CH2, SEM), 5.2 (d, 1H, CH2, SEM),
5.3–5.3 (m, 2H, CH2, SEM), 6.2 (t, J = 7 Hz, 1H, 1ꢁ), 6.3 (t, 1H, 1ꢁ), 7.6
(s, 1H, base); 13C NMR (CDCl3): δ −5.5 (CH3), −5.3 (CH3), −4.8 (CH3),
−4.7 (CH3), −1.47 (CH3), −1.43 (CH3), 17.93 (Cquat), 18.01 (CH3), 18.0
(CH3), 18.3 (Cquat), 21.7 (CH3), 25.7 (CH3), 25.9 (CH3), 32.0 (CH2), 37.6
(CH2), 41.1 (CH2), 42.4 (Cquat), 45.0 (CH2-base), 62.5 (CH2), 63.3 (CH2),
66.7 (CH2), 67.7 (CH2), 70.0 (CH2), 70.3 (CH2), 71.8 (CH), 72.8 (CH),
85.3 (CH), 86.1 (CH), 86.4 (CH), 88.2 (CH), 108.4 (Cquat), 138.9 (CH),
150.3 (Cquat), 152.9 (Cquat), 164.0 (Cquat), 173.5 (Cquat); HRMS: m/z:
973.5215 (calcd. for C44 H85 N4 O12 Si4; 973.5241) (M + H); MS: (TOF, MS,
ESI) m/z 996, 973, 973, 947, 946, 945, 917, 829, 801, 729.
Compound 7. Mono TBDMS dinucleoside was isolated from the
deprotection reaction of 3 using 4% HF:Pyridine. Yield: 32%; white solid;
1
Rf. 0.7; H NMR (CDCl3): δ −0.0 (s, 9H, SiCH3), −0.0 (s, 9H, SiCH3),
−0.06 (s, 9H, CH3, TBDMS), 0.8 (s, 6H, SiCH3, TBDMS), 0.8–0.9 (m, 4H,
CH2), 1.1 (s, 3H, Me, C5), 2.0–2.0 (m, 1H, CH2, 2ꢁ), 2.1–2.2 (m, 2H, CH,
2ꢁ), 2.3–2.3 (m, 1H, CH, 2), 2.6 (d, J = 14.5 Hz, 1H, CH2, bridge), 2.7 (d, J
= 14.5 Hz, 1H, CH2 bridge), 3.1 (d, J = 13 Hz, 1H, CH2, base), 3.4 (d, J =
13 Hz, 1H, CH2, base), 3.5 (t, J = 8 Hz, 2H, CH2, SEM), 3.6 (t, J = 9 Hz,
2H, CH2, SEM), 3.6–3.7 (m, 3H, CH2, 5ꢁ), 3.8 (bt, 1H, 4ꢁ), 3.9 (d, J = 11 Hz,
1H, 5ꢁ), 4.0 (bt, 1H, CH, 4ꢁ), 4.4 (bt, 1H, 3ꢁ), 4.4 (bt, 1H, 3ꢁ), 5.1–5.1 (m,
2H, CH2, SEM), 5.2 (d, J = 10 Hz, 1H, CH2, SEM), 5.3 (d, J = 9.5Hz, 1H,
CH2, SEM), 6.1–6.1 (m, 2H, 1), 7.8 (s, 1H, base); 13C NMR (CDCl3): δ−4.9
(CH3),−4.7 (CH3), −1.5 (CH3), 17.9 (CH2) 18.05 (CH2), 21.45 (CH3), 25.6
(CH3), 31.7 (CH2), 37.1 (CH2), 41.8 (CH2), 42.4, 45.15 (CH2-base), 61.8
(CH2), 62.5 (CH2), 66.9 (CH2), 67.6 (CH2), 69.8 (CH2), 70.1 (CH2), 71.7
(CH), 72.37 (CH), 85.63 (CH), 86.02 (CH), 87.52 (CH), 88.5 (CH), 107.5
(Cquat), 139.98 (CH), 150.4 (Cquat), 152.1 (Cquat), 163.9 (Cquat), 174.5
(Cquat); HRMS: m/z: 859.4369 (calcd. for C38 H71 N4 O12 Si3; 859.4376) (M
+ H); MS: (TOF, MS, ESI) m/z 882, 881, 831, 803, 715, 687, 615, 597, 543.
3ꢁ-O-tert-butyldimethylsilyl-thymidine 14: Yield: 72%; white solid; Rf. 0.2;
1H NMR (CDCl3): δ −0.07 (s, 9H, TBDMS),−0.8 (s, 6H, SiCH3, TBDMS),
1.8 (s, 3H, Me, C5), 2.05–2.0 (m, 1H, CH2, 2ꢁ), 2.3–2.38 (m, 1H, CH, 2ꢁ),
3.3 (s, 1H, OH), 3.79 (d, J = 13 Hz, 1H, CH2, 5), 3.85 (d, J = 13 Hz, 1H,
CH2, 5), 4.0 (s, 1H), 4.4 (s, 1H), 6.3 (t, 1H, 1), 7.52 (s, 1H, C6); 13C NMR
(CDCl3): δ−5.4 (CH3),−5.3 (CH3), 12.53 (CH3), 18.34 (CH2) 25.9 (CH3),
41.1 (CH2), 63.6 (CH2), 72.5 (CH), 85.0 (CH), 87.1 (CH), 110.9 (Cquat),
135.5 (CH), 150.6 (Cquat), 164.0 (Cquat); MS: (TOF, MS, ESI) m/z 357,
342.

1028
T. Chandra et al.
5ꢁ-O-triethylsilyl-adenosine 16: A solution of adenosine 3 (0.300 g, 1.19
mmol) in DMF (3 mL) was stirred at room temperature for 5 minutes
followed by dropwise addition of a solution of triethylsilyl chloride (0.163
g, 1.0 mmol) in DMF (3 mL). After complete addition the reaction
mixture was stirred for 8 hours at room temperature. Upon complete
triethylsilylation, the solvent was removed under reduced pressure. The
residue was dissolved in methylene chloride and washed with saturated
sodium bicarbonate solution. The methylene chloride layer was dried
over anhydrous sodium sulfate, concentrated, and finally the residue was
purified on a silica gel column (flash chromatography) using a mix-
ture of methanol: methylene chloride (10:90), resulting in the desired
product as a white fluffy solid with 85% yield. White solid; Rf. 0.2;
1H NMR (CDCl3): δ 0.48 (q, 6H, 3CH2), 0.83 (t, J = 7.5 Hz, 9H,
3CH3), 2.25–2.3 (m, 1H, CH2, 2ꢁ), 2.6–2.7 (m, 1H, CH2, 2ꢁ), 3.64 (dd,
J = 4/7 Hz, 1H, 5), 3.75 (dd, J = 4/7 Hz, 1H, CH2, 5ꢁ), 3.9 (d, J = 3.5
Hz, 1H), 4.3 (bt, 1H), 5.3 (d, 1H), 6.3 (t, 1H, 1ꢁ), 8.0 (s, 1H), 8.2 (s, 1H);
13C NMR (CDCl3): δ 3.8 (CH2), 6.6 (CH2), 39.0 (CH2) 62.8 (CH2), 70.4
(CH), 83.3 (CH), 87.2 (CH), 119.1 (Cquat), 139.5 (CH), 149.14 (Cquat),
152.5 (CH), 156.0 (Cquat).
3ꢁ-O-tert-butyldimethylsilyl-5ꢁ-O-triethylsilyl-adenosine 17: Viscous oil; Rf.
0.5; 1H NMR (CDCl3): δ 0.05 (s, 6H, TBDMS), 0.59 (q, 6H, 3CH2), 0.87 (s,
9H, TBDMS) 0.94 (t, J = 7.5 Hz, 9H, 3CH3), 2.38–2.4 (m, 1H, CH2, 2ꢁ),
2.5–2.6 (m, 1H, CH2, 2ꢁ), 3.7 (dd, J = 4/7 Hz, 1H, 5ꢁ), 3.8 (dd, J = 4/7 Hz,
1H, CH2, 5ꢁ), 3.9 (bt, 1H), 4.5 (bt, 1H), 5.3 (d, 1H), 6.32 (bs, 2H, NH2), 6.4
(m, 1H, 1), 8.1 (s, 1H), 8.2 (s, 1H).
1
3ꢁ-O-tert-butyldimethylsilyl-adenosine 18: White solid; Rf. 0.3; H NMR
(DMSO-d6): δ 0.0 (s, 6H, TBDMS), 0.87 (s, 9H, TBDMS) 2.2–2.3 (m, 1H,
CH2, 2ꢁ), 2.6–2.6 (m, 1H, CH2, 2ꢁ), 3.65 (dd, J = 4/7 Hz, 1H, 5), 3.7 (dd, J
= 4/7 Hz, 1H, CH2, 5ꢁ), 3.8 (m, 1H), 4.29 (bt, 1H), 5.4 (s, 1H, OH), 6.3 (m,
1H, 1), 6.32 (bs, 2H, NH2), 8.1 (s, 1H), 8.2 (s, 1H).
N3-Trimethylsilylethoxymethyl-thymidine 23: Yield: 76%; white solid; Rf.
1
0.2; H NMR (CDCl3): δ −0.05 (s, 9H, SEM),−0.09 (t, 2H, SEM), 1.8 (s,
3H, Me, C5ꢁ), 2.3 (t, 2H, CH2, 2ꢁ), 3.1 (bs, 1H, OH), 3.3 (bs, 1H, OH), 3.6
(t, 2H, SEM), 3.79 (d, J = 13 Hz, 1H, CH2, 5ꢁ), 3.85 (d, J = 13 Hz, 1H,
CH2, 5ꢁ), 3.9 (bt, 1H), 4.51 (bt, 1H), 5.3 (s, 2H, SEM), 6.1 (t, 1H, 1ꢁ), 7.4
(s, 1H, C6); 13C NMR (CDCl3): δ−1.4 (CH3), 13.2 (CH3), 18.1 (CH2) 40.1
(CH2), 62.1 (CH2), 67.7, 70.1, 71.1, 86.9, 110.3 (Cquat), 135.5 (CH), 151.0
(Cquat), 163.0 (Cquat); MS: (TOF, MS, ESI) m/z 373, 372.
CONCLUSION
In summary, we describe here a simple methodology for the de-
protection of TES ethers to the corresponding alcohols with control of
chemoselectivity. A published method for deprotection of TES ethers using

Chemoselective Deprotection of triethylsilyl Ethers
1029
HF:pyridine resulted in low yields of the desired dinucleosides. However,
we found that TES ethers are selectively deprotected to the corresponding
alcohols in high yields using formic acid in methanol under mild reaction
conditions. In addition, the protected 5R and 5S-dinucleosides were easily
prepared and purified on a silica gel column.
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